1. Field of the Invention
The present invention relates to the area of cyclic tetraamines and, more particularly, relates to an improved process for preparing a specific cyclic tetraamine which is a valuable starting material in the preparation of a specific pharmaceutically active 1,4-phenylenebis-(methylene)-linked cyclam dimer.
2. Description of the Prior Art
U.S. Pat. No. 5,021,409 is directed to a method of treating retroviral infections comprising administering to a mammal in need of such treatment a therapeutically effective amount of a bicyclic macrocyclic polyamine compound. Although the usefulness of certain alkylene and arylene bridged cyclam dimers is generically embraced by the teachings of the reference, no arylene bridged cyclam dimers are specifically disclosed. In addition, although no specific processes are set forth for preparing the alkylene and arylene bridged cyclam dimers, it is believed that at least some of them are prepared employing 1,4,8,11-tetraazacyclotetradecane (aka. cyclam) as the starting material.
WO 93/12096 discloses the usefulness of certain linked cyclic polyamines in combating HIV and pharmaceutical compositions useful therefor. Among the specifically disclosed compounds is 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane (and its acid addition salts),which compound is a highly potent inhibitor of several strains of human immune deficiency virus type 1 (HIV-1) and type 2 (HIV-2). Although no specific processes are set forth for preparing said compound, it is believed to be prepared employing 1,4,8,11-tetraazacyclotetradecane as the starting material.
European Patent Appln. 374,929 discloses a process for preparing mono-N-alkylated polyazamacrocycles comprising reacting the unprotected macrocycle with an electrophile in a non-polar, relatively aprotic solvent in the absence of base. Although one of the specifically disclosed macrocycles is 1,4,8,11-tetraazacyclotetradecane, it is indicated 1to have been purchased commercially from Aldrich Chemical Co.
U.S. Pat. No. 5,047,527 is directed to a process for preparing a monofunctionalized (e.g., monoalkylated)cyclic tetraamine comprising: 1) reacting the unprotected macrocycle with chromium hexacarbonyl to obtain a triprotected tetraazacycloalkane compound; 2) reacting the free amine group of the triprotected compound prepared in 1) with an organic (e.g., alkyl) halide to obtain a triprotected monofunctionalized (e.g., monoalkylated) tetraazacycloalkane compound; and 3) de-protecting the compound prepared in 2) by simple air oxidation at acid pH to obtain the desired compound. In addition, the reference discloses alterative methods of triprotection employing boron and phosphorous derivatives and the preparation of linked compounds, including the cyclam dimer 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane, by reacting triprotected cyclam prepared as set forth in 1) above with an organic dihalide in a molar ratio of 2:1, and deprotecting the resultant compound to obtain the desired cyclam dimer. Although one of the specifically disclosed macrocycles is cyclam, since no mention is made regarding its method of preparation, it is believed to have been obtained commercially.
J. Med. Chem., Vol. 38, No. 2, pgs. 366-378 (1995) is directed to the synthesis and anti-HIV activity of a series of novel phenylenebis(methylene)-linked bis-tetraazamacrocyclic analogs, including the known cyclam dimer 1,1'-[1,4-phenylenebis(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. The cyclam dimers disclosed in this reference, including the afore-mentioned cyclam dimer, are prepared by: 1) forming the tritosylate of the tetraazamacrocycle; 2) reacting the protected tetraazamacrocycle with an organic dihalide, e.g., dibromo-p-xylene, in acetonitrile in the presence of a base such as potassium carbonate; and 3) de-protecting the bis-tetraazamacrocycle prepared in 2) employing fleshly prepared sodium amalgam, concentrated sulfuric acid or an acetic acid/hydrobromic acid mixture to obtain the desired cyclam dimer, or an acid addition salt thereof. Although one of the specifically disclosed macrocycles is cyclam, it is indicated to have been obtained commercially.
From the above, it is clear that the compound 1,4,8,11-tetraazacyclotetradecane (aka. cyclam) is a valuable starting material in the preparation of a number of pharmacologically active compounds, including the highly potent anti-HIV compound 1,1'-[1,4-phenylenebis-(methylene)]-bis-1,4,8,11-tetraazacyclotetradecane. However, since cyclam is expensive and not readily available, there was a need to develop a more practical process for preparing 1,4,8,11 -tetraazacyclotetradecane.